2-190881158-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS1_Supporting

The NM_014905.5(GLS):c.74T>G(p.Leu25Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,546,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

GLS
NM_014905.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93

Publications

2 publications found

Variant links:

Genes affected

GLS (HGNC:4331): (glutaminase) This gene encodes the K-type mitochondrial glutaminase. The encoded protein is an phosphate-activated amidohydrolase that catalyzes the hydrolysis of glutamine to glutamate and ammonia. This protein is primarily expressed in the brain and kidney plays an essential role in generating energy for metabolism, synthesizing the brain neurotransmitter glutamate and maintaining acid-base balance in the kidney. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

GLS Gene-Disease associations (from GenCC):

glutaminase deficiency
Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
global developmental delay, progressive ataxia, and elevated glutamine
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
developmental and epileptic encephalopathy, 71
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

GLS links:

ENSG00000228509 (HGNC:):

ENSG00000228509 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000395 (6/151838) while in subpopulation AMR AF = 0.000328 (5/15260). AF 95% confidence interval is 0.000129. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014905.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLS	NM_014905.5	MANE Select	c.74T>G	p.Leu25Arg	missense	Exon 1 of 18	NP_055720.3
GLS	NM_001437282.1		c.74T>G	p.Leu25Arg	missense	Exon 1 of 17	NP_001424211.1	H7C201
GLS	NM_001256310.2		c.74T>G	p.Leu25Arg	missense	Exon 1 of 15	NP_001243239.1	O94925-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLS	ENST00000320717.8	TSL:1 MANE Select	c.74T>G	p.Leu25Arg	missense	Exon 1 of 18	ENSP00000317379.3	O94925-1
GLS	ENST00000338435.9	TSL:1	c.74T>G	p.Leu25Arg	missense	Exon 1 of 15	ENSP00000340689.4	O94925-3
GLS	ENST00000479552.1	TSL:1	n.287T>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000834

AC:

AN:

143882

AF XY:

0.0000622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000307

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000681

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000918

AC:

128

AN:

1394306

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

690372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31340

American (AMR)

AF:

0.000529

AC:

AN:

37796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24664

East Asian (EAS)

AF:

0.00

AC:

AN:

35536

South Asian (SAS)

AF:

0.00

AC:

AN:

80312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.0000939

AC:

102

AN:

1086238

Other (OTH)

AF:

0.000104

AC:

AN:

57922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151838

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41392

American (AMR)

AF:

0.000328

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000870

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000192

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Benign

0.18

Eigen_PC

Benign

0.081

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.20

PhyloP100

1.9

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.78

REVEL

Benign

0.20

Sift

Uncertain

0.0080

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.75

MutPred

0.32

Gain of methylation at L25 (P = 0.0197)

MVP

0.66

MPC

1.5

ClinPred

0.21

GERP RS

4.1

PromoterAI

0.046

Neutral

(source)

Varity_R

0.48

gMVP

0.35

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over